In a computational model of LQT3, beta-activation suppressed arrhythmogenic phenomena dose-dependently, while low-dose propranolol reversed these benefits and high-dose decreased susceptibility.
Do beta-adrenergic agonists and antagonists alter arrhythmogenic phenomena in a computational model of LQT3?
Computational modeling suggests beta-activation may be protective in LQT3, indicating that standard beta-blocker therapy might be detrimental at low doses and requires careful clinical re-evaluation.
AIMS: Long QT syndrome (LQTS) is a heterogeneous collection of inherited cardiac ion channelopathies characterized by a prolonged electrocardiogram QT interval and increased risk of sudden cardiac death. Beta-adrenergic blockers are the mainstay of treatment for LQTS. While their efficacy has been demonstrated in LQTS patients harbouring potassium channel mutations, studies of beta-blockers in subtype 3 (LQT3), which is caused by sodium channel mutations, have produced ambiguous results. In this modelling study, we explore the effects of beta-adrenergic drugs on the LQT3 phenotype. METHODS AND RESULTS: In order to investigate the effects of beta-adrenergic activity and to identify sources of ambiguity in earlier studies, we developed a computational model incorporating the effects of beta-agonists and beta-blockers into an LQT3 mutant guinea pig ventricular myocyte model. Beta-activation suppressed two arrhythmogenic phenomena, transmural dispersion of repolarization and early after depolarizations, in a dose-dependent manner. However, the ability of beta-activation to prevent cardiac conduction block was pacing-rate-dependent. Low-dose beta-blockade by propranolol reversed the beneficial effects of beta-activation, while high dose (which has off-target sodium channel effects) decreased arrhythmia susceptibility. CONCLUSION: These results demonstrate that beta-activation may be protective in LQT3 and help to reconcile seemingly conflicting results from different experimental models. They also highlight the need for well-controlled clinical investigations re-evaluating the use of beta-blockers in LQT3 patients.
Ahrens‐Nicklas et al. (Thu,) conducted a other in Long QT-3 syndrome (LQT3). Beta-agonists and beta-blockers (propranolol) was evaluated on Arrhythmogenic phenomena (transmural dispersion of repolarization and early after depolarizations). In a computational model of LQT3, beta-activation suppressed arrhythmogenic phenomena dose-dependently, while low-dose propranolol reversed these benefits and high-dose decreased susceptibility.